Reducing the Incidence of Nevirapine Resistance Mutations in Pregnant HIV Infected Women Who Receive Anti-HIV Drugs Prior to and After Giving Birth

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ClinicalTrials.gov Identifier: NCT00109590

Recruitment Status
:
Completed

First Posted
: May 2, 2005

Results First Posted
: November 6, 2012

Last Update Posted
: January 13, 2015

Sponsor:

National Institute of Allergy and Infectious Diseases (NIAID)

Collaborator:

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

The purpose of this study is to determine which of 3 different anti-HIV drug regimens given to HIV infected pregnant women during and after their pregnancies is most effective in reducing the incidence of nevirapine (NVP) resistance mutations. Blood levels of NVP and lopinavir/ritonavir (LPV/r) will also be studied.

Study hypothesis: NVP resistance following single-dose NVP can be prevented with the concomitant administration of additional antiretroviral therapy (ART).

A single dose of nevirapine (SD-NVP) given to an HIV infected pregnant woman in labor followed by a single dose to her infant had been shown to be a simple and effective means of reducing mother-to-child transmission (MTCT) of HIV among women who had not received antiretroviral (ART) during pregnancy. However, development of NVP and other nonnucleoside reverse transcriptase inhibitor (NNRTI)-resistant virus was a concern. An optimal ART regimen that can prevent selection of resistant virus while efficiently preventing MTCT was needed. This study evaluated 3 different ART strategies for preventing the development of NVP resistance in HIV infected pregnant women and compared the incidence of NVP resistance mutations postpartum observed with each regimen to the incidence among historical controls. NVP and LPV/r pharmacokinetics (PK) were also evaluated in this study.

Participants were randomly assigned to one of three study arms. All study participants received a single dose of oral NVP at the onset of labor and, oral zidovudine (ZDV) at the onset of labor, and every three hours during labor. Arm A: (LPV/r x 7d) participants received enteric-coated didanosine (ddI) and LPV/r orally twice daily beginning at the onset of labor and continuing through 7 days postpartum; oral ZDV was also taken twice daily for 7 days postpartum. Arm B: (no LPV/r) participants received enteric-coated ddI beginning at the onset of labor and continued through 30 days postpartum; oral ZDV was also taken twice daily for 30 days postpartum. Arm C : (LPV/r x 30d) participants received enteric-coated ddI and LPV/r orally twice daily beginning at the onset of labor and continued through 30 days postpartum; oral ZDV was also taken twice daily for 30 days postpartum.

All women were followed for at least 24 weeks postpartum. Women with resistance mutations identified within 8 weeks postpartum were to be followed until 72 weeks postpartum to evaluate the persistence of the mutations. All infants were followed until at least 12 weeks of age. HIV-infected infants were to be followed until 24 weeks of age. There were 11 study visits for women at day 10, 21, and 30 and week 5, 6, 8, 12, 24, 36, 48, and 72. Medical history assessment, a physical exam, and blood collection occurred at all visits. Blood collection for PK studies occurred at Days 10, 21, and 30. All women were asked to complete an adherence questionnaire at Day 10; women assigned to Arms A : LPV/r x 7d and B: no LPV/r were also asked to complete an adherence questionnaire at Day 30. There were 6 study visits for infants at birth - 48 hours, day 21, week 5, 12, 16 and 24. Medical history assessment and a physical exam occurred at most visits; blood collection occurred at all visits.

Data and specimens for the historical control comparison group were obtained from the PHPT-2 trial*, in which five of the P1032 study sites had participated between 2001 and 2003. PHPT-2 was a study of the efficacy of SD-NVP to prevent MTCT among women who received ZDV after 27 weeks gestation but no postpartum ART. Criteria for inclusion in the historical comparison group included receipt of SD-NVP, a CD4 count of more than 250 cells per cubic millimeter within 30 days of screening or entry, and the availability of plasma samples at 10 days or 6 weeks post-partum.

Phase II Study of the Pharmacokinetics of Nevirapine and the Incidence of Nevirapine Resistance Mutations in HIV-Infected Women Receiving a Single Intrapartum Dose of Nevirapine With the Concomitant Administration of Zidovudine/Didanosine or Zidovudine/Didanosine/Lopinavir/Ritonavir

The Proportion of Women Who Develop One or More New NVP Resistance Mutations as Identified by Consensus Sequencing or Oligonucleotide Ligation Assay in Plasma (Sampling Was Done at Days 10,21,30, and Weeks 5,6, and 8 Postpartum). [ Time Frame: within 8 weeks postpartum. ]

The incidence of new NVP resistance mutation in plasma HIV within 8 weeks postpartum in each randomized arm was estimated using an exact binomial confidence interval. If a resistance mutation was detected at any of the timepoints then an endpoint was met. Samples with VL <500 copies/mL were considered free of mutations. If a resistance result was missing for reasons other than VL <500 copies/ml (e.g.missed visit), it was conservatively imputed as resistant in the primary analysis.

The Proportion of Women in Each Randomized Arm Who Have One or More New NVP Resistance Mutations as Identified by Consensus Sequencing or Oligonucleotide Ligation Assay (OLA) in Plasma [ Time Frame: at Day 10 or Week 6 postpartum. ]

The incidence of new NVP resistance mutations at day 10 or week 6 postpartum in each randomized arm. Samples with viral load <500 copies/mL were considered free of mutations. If a resistance result was missing for reasons other than VL <500 copies/ml it was conservatively imputed as resistant in the primary analysis.

Area Under the Curve Pharmacokinetic Outcome for LPV/r. (AUC ug*hr/mL) [ Time Frame: Within 72 hours postpartum and during the first 30 days postpartum ]

Data was analyzed with WinNonLin (Version 5.2, Pharsight, USA) using non-compartmental methods. The pharmacokinetic parameters were calculated using the linear-trapezoidal rule. Cpredose and C4hour at the two measurement times were compared within-subject using the Wilcoxon signed-rank test.

Maximum Concentration Pharmacokinetic Outcome for LPV/r (Cmax ug/mL) . [ Time Frame: Within 72 hours postpartum and during the first 30 days postpartum ]

Data was analyzed with WinNonLin (Version 5.2, Pharsight, USA) using non-compartmental methods. The pharmacokinetic parameters were calculated using the linear-trapezoidal rule. Cpredose and C4hour at the two measurement times were compared within-subject using the Wilcoxon signed-rank test.

Pre-dose Concentration Pharmacokinetic Outcome for LPV/r (Cpredose ug/mL). [ Time Frame: Within 72 hours postpartum and during the first 30 days postpartum ]

Data was analyzed with WinNonLin (Version 5.2, Pharsight, USA) using non-compartmental methods. The pharmacokinetic parameters were calculated using the linear-trapezoidal rule. Cpredose and C4hour at the two measurement times were compared within-subject using the Wilcoxon signed-rank test.

Four (4) Hour Concentration Pharmacokinetic Outcome for LPV/r (C4hour ug/mL). [ Time Frame: Within 72 hours postpartum and during the first 30 days postpartum ]

Data was analyzed with WinNonLin (Version 5.2, Pharsight, USA) using non-compartmental methods. The pharmacokinetic parameters were calculated using the linear-trapezoidal rule. Cpredose and C4hour at the two measurement times were compared within-subject using the Wilcoxon signed-rank test.

Secondary Outcome Measures
:

The Proportion of Women in Each Randomized Arm Who Have One or More New NVP Resistance Mutations for the Subgroup of Women With Plasma HIV RNA >= 500 Copies/ml At Entry [ Time Frame: at Day 10 or Week 6 postpartum. ]

The incidence of new NVP resistance mutations at day 10 or week 6 postpartum in each randomized arm. Samples with viral load <500 copies/mL were considered free of mutations. If a resistance result was missing for reasons other than VL <500 copies/ml it was conservatively imputed as resistant in the primary analysis.

The Proportion of Women With Any New ZDV, ddI, or LPV/r Resistance Mutations. [ Time Frame: At Week 5 postpartum (ZDV) and at the first timepoint with viral load >=500 copies/ml after treatment discontinuation (ddI and LPV/r). ]

Number of Women With Grade >=3 Events After Start of Study Treatment [ Time Frame: After start of study Treatment (postpartum) ]

Adverse events were graded using the Division of AIDS (DAIDS) Table for Grading

> the Severity of Adult and Pediatric Adverse Events (December 2004). All grade 3 and higher signs, symptoms, and laboratory toxicities (and events of any grade that led to a change in study treatment) were included.

Proportion of Women With New NVP Resistance Mutation Within 8 Weeks Postpartum Who Had a NVP Resistance Mutation Detected at 72 Weeks Postpartum. [ Time Frame: within 72 weeks postpartum ]

Resistance mutations as identified by OLA in plasma samples or PBMC at 72 weeks postpartum amongst women who had new NVP resistance mutations within 8 weeks postpatrum. These results were based on the 13 women who developed a new NVP resistance mutation in the first 8 weeks postpartum. For the primary outcome measure 1, one particpant in arm A was unavailable for follow-up after week 5 and was conservatively imputed to have developed resistance mutation.

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Ages Eligible for Study:

18 Years and older (Adult, Senior)

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

No

Criteria

Inclusion Criteria for Mothers:

HIV infected

Pregnant with a viable fetus

Between 28 and 38 weeks of pregnancy

CD4 count greater than 250 cells/mm3 within 30 days prior to study entry

Able to receive oral ART during labor

Willing to use acceptable forms of contraception while on study treatment

Able to provide written informed consent

Exclusion Criteria for Mothers:

Known allergy or hypersensitivity to ddI, LPV, NVP, ritonavir (RTV), or ZDV

Any ART other than ZDV during a previous pregnancy or the current pregnancy

Certain medications

Planning to receive additional ART during the first 8 weeks postpartum

Planning to breastfeed

Unlikely to comply with postpartum study requirements, in the opinion of the investigator